Publications by authors named "Ben R Hopkins"

9 Publications

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Evolution of sexual development and sexual dimorphism in insects.

Curr Opin Genet Dev 2021 Apr 10;69:129-139. Epub 2021 Apr 10.

Department of Evolution and Ecology, University of California, One Shields Ave, Davis, CA, 95616, USA.

Most animal species consist of two distinct sexes. At the morphological, physiological, and behavioral levels the differences between males and females are numerous and dramatic, yet at the genomic level they are often slight or absent. This disconnect is overcome because simple genetic differences or environmental signals are able to direct the sex-specific expression of a shared genome. A canonical picture of how this process works in insects emerged from decades of work on Drosophila. But recent years have seen an explosion of molecular-genetic and developmental work on a broad range of insects. Drawing these studies together, we describe the evolution of sexual dimorphism from a comparative perspective and argue that insect sex determination and differentiation systems are composites of rapidly evolving and highly conserved elements.
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http://dx.doi.org/10.1016/j.gde.2021.02.011DOI Listing
April 2021

Sex Peptide controls the assembly of lipid microcarriers in seminal fluid.

Proc Natl Acad Sci U S A 2021 Feb;118(5)

Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3QX Oxford, United Kingdom;

Seminal fluid plays an essential role in promoting male reproductive success and modulating female physiology and behavior. In the fruit fly, , Sex Peptide (SP) is the best-characterized protein mediator of these effects. It is secreted from the paired male accessory glands (AGs), which, like the mammalian prostate and seminal vesicles, generate most of the seminal fluid contents. After mating, SP binds to spermatozoa and is retained in the female sperm storage organs. It is gradually released by proteolytic cleavage and induces several long-term postmating responses, including increased ovulation, elevated feeding, and reduced receptivity to remating, primarily signaling through the SP receptor (SPR). Here, we demonstrate a previously unsuspected SPR-independent function for SP. We show that, in the AG lumen, SP and secreted proteins with membrane-binding anchors are carried on abundant, large neutral lipid-containing microcarriers, also found in other SP-expressing species. These microcarriers are transferred to females during mating where they rapidly disassemble. Remarkably, SP is a key microcarrier assembly and disassembly factor. Its absence leads to major changes in the seminal proteome transferred to females upon mating. Males expressing nonfunctional SP mutant proteins that affect SP's binding to and release from sperm in females also do not produce normal microcarriers, suggesting that this male-specific defect contributes to the resulting widespread abnormalities in ejaculate function. Our data therefore reveal a role for SP in formation of seminal macromolecular assemblies, which may explain the presence of SP in species that lack the signaling functions seen in .
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http://dx.doi.org/10.1073/pnas.2019622118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865141PMC
February 2021

Male reproductive aging arises via multifaceted mating-dependent sperm and seminal proteome declines, but is postponable in .

Proc Natl Acad Sci U S A 2020 07 1;117(29):17094-17103. Epub 2020 Jul 1.

Department of Zoology, University of Oxford, OX1 3SZ Oxford, United Kingdom.

Declining ejaculate performance with male age is taxonomically widespread and has broad fitness consequences. Ejaculate success requires fully functional germline (sperm) and soma (seminal fluid) components. However, some aging theories predict that resources should be preferentially diverted to the germline at the expense of the soma, suggesting differential impacts of aging on sperm and seminal fluid and trade-offs between them or, more broadly, between reproduction and lifespan. While harmful effects of male age on sperm are well known, we do not know how much seminal fluid deteriorates in comparison. Moreover, given the predicted trade-offs, it remains unclear whether systemic lifespan-extending interventions could ameliorate the declining performance of the ejaculate as a whole. Here, we address these problems using We demonstrate that seminal fluid deterioration contributes to male reproductive decline via mating-dependent mechanisms that include posttranslational modifications to seminal proteins and altered seminal proteome composition and transfer. Additionally, we find that sperm production declines chronologically with age, invariant to mating activity such that older multiply mated males become infertile principally via reduced sperm transfer and viability. Our data, therefore, support the idea that both germline and soma components of the ejaculate contribute to male reproductive aging but reveal a mismatch in their aging patterns. Our data do not generally support the idea that the germline is prioritized over soma, at least, within the ejaculate. Moreover, we find that lifespan-extending systemic down-regulation of insulin signaling results in improved late-life ejaculate performance, indicating simultaneous amelioration of both somatic and reproductive aging.
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http://dx.doi.org/10.1073/pnas.2009053117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382285PMC
July 2020

Structural variation in spermathecal ducts and its association with sperm competition dynamics.

R Soc Open Sci 2020 Mar 25;7(3):200130. Epub 2020 Mar 25.

Department of Zoology, University of Oxford, Oxford OX1 3SZ, UK.

The ability of female insects to retain and use sperm for days, months, or even years after mating requires specialized storage organs in the reproductive tract. In most orders, these organs include a pair of sclerotized capsules known as spermathecae. Here, we report that some females exhibit previously uncharacterized structures within the distal portion of the muscular duct that links a spermatheca to the uterus. We find that these 'spermathecal duct presences' (SDPs) may form in either or both ducts and can extend from the duct into the sperm-storing capsule itself. We further find that the incidence of SDPs varies significantly between genotypes, but does not change significantly with the age or mating status of females, the latter indicating that SDPs are not composed of or stimulated by sperm or male seminal proteins. We show that SDPs affect neither the number of first male sperm held in a spermatheca nor the number of offspring produced after a single mating. However, we find evidence that SDPs are associated with a lack of second male sperm in the spermathecae after females remate. This raises the possibility that SDPs provide a mechanism for variation in sperm competition outcome among females.
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http://dx.doi.org/10.1098/rsos.200130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137968PMC
March 2020

BMP signaling inhibition in secondary cells remodels the seminal proteome and self and rival ejaculate functions.

Proc Natl Acad Sci U S A 2019 12 18;116(49):24719-24728. Epub 2019 Nov 18.

Edward Grey Institute, Department of Zoology, University of Oxford, OX1 3PS Oxford, United Kingdom.

Seminal fluid proteins (SFPs) exert potent effects on male and female fitness. Rapidly evolving and molecularly diverse, they derive from multiple male secretory cells and tissues. In , most SFPs are produced in the accessory glands, which are composed of ∼1,000 fertility-enhancing "main cells" and ∼40 more functionally cryptic "secondary cells." Inhibition of bone morphogenetic protein (BMP) signaling in secondary cells suppresses secretion, leading to a unique uncoupling of normal female postmating responses to the ejaculate: refractoriness stimulation is impaired, but offspring production is not. Secondary-cell secretions might therefore make highly specific contributions to the seminal proteome and ejaculate function; alternatively, they might regulate more global-but hitherto undiscovered-SFP functions and proteome composition. Here, we present data that support the latter model. We show that in addition to previously reported phenotypes, secondary-cell-specific BMP signaling inhibition compromises sperm storage and increases female sperm use efficiency. It also impacts second male sperm, tending to slow entry into storage and delay ejection. First male paternity is enhanced, which suggests a constraint on ejaculate evolution whereby high female refractoriness and sperm competitiveness are mutually exclusive. Using quantitative proteomics, we reveal changes to the seminal proteome that surprisingly encompass alterations to main-cell-derived proteins, indicating important cross-talk between classes of SFP-secreting cells. Our results demonstrate that ejaculate composition and function emerge from the integrated action of multiple secretory cell types, suggesting that modification to the cellular make-up of seminal-fluid-producing tissues is an important factor in ejaculate evolution.
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http://dx.doi.org/10.1073/pnas.1914491116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900634PMC
December 2019

Divergent allocation of sperm and the seminal proteome along a competition gradient in .

Proc Natl Acad Sci U S A 2019 09 20;116(36):17925-17933. Epub 2019 Aug 20.

Edward Grey Institute, Department of Zoology, University of Oxford, OX1 3PS Oxford, United Kingdom.

Sperm competition favors large, costly ejaculates, and theory predicts the evolution of allocation strategies that enable males to plastically tailor ejaculate expenditure to sperm competition threat. While greater sperm transfer in response to a perceived increase in the risk of sperm competition is well-supported, we have a poor understanding of whether males () respond to changes in perceived intensity of sperm competition, () use the same allocation rules for sperm and seminal fluid, and () experience changes in current and future reproductive performance as a result of ejaculate compositional changes. Combining quantitative proteomics with fluorescent sperm labeling, we show that males exercise independent control over the transfer of sperm and seminal fluid proteins (SFPs) under different levels of male-male competition. While sperm transfer peaks at low competition, consistent with some theoretical predictions based on sperm competition intensity, the abundance of transferred SFPs generally increases at high competition levels. However, we find that clusters of SFPs vary in the directionality and sensitivity of their response to competition, promoting compositional change in seminal fluid. By tracking the degree of decline in male mating probability and offspring production across successive matings, we provide evidence that ejaculate compositional change represents an adaptive response to current sperm competition, but one that comes at a cost to future mating performance. Our work reveals a previously unknown divergence in ejaculate component allocation rules, exposes downstream costs of elevated ejaculate investment, and ultimately suggests a central role for ejaculate compositional plasticity in sexual selection.
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http://dx.doi.org/10.1073/pnas.1906149116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731677PMC
September 2019

Quantitative Proteomics Identification of Seminal Fluid Proteins in Male .

Mol Cell Proteomics 2019 03 4;18(Suppl 1):S46-S58. Epub 2018 Oct 4.

From the ‡Edward Grey Institute, Department of Zoology, University of Oxford, Oxford, UK.

Seminal fluid contains some of the fastest evolving proteins currently known. These seminal fluid proteins (Sfps) play crucial roles in reproduction, such as supporting sperm function, and particularly in insects, modifying female physiology and behavior. Identification of Sfps in small animals is challenging, and often relies on samples taken from the female reproductive tract after mating. A key pitfall of this method is that it might miss Sfps that are of low abundance because of dilution in the female-derived sample or rapid processing in females. Here we present a new and complementary method, which provides added sensitivity to Sfp identification. We applied label-free quantitative proteomics to , male reproductive tissue - where Sfps are unprocessed, and highly abundant - and quantified Sfps before and immediately after mating, to infer those transferred during copulation. We also analyzed female reproductive tracts immediately before and after copulation to confirm the presence and abundance of known and candidate Sfps, where possible. Results were cross-referenced with transcriptomic and sequence databases to improve confidence in Sfp detection. Our data were consistent with 125 previously reported Sfps. We found nine high-confidence novel candidate Sfps, which were both depleted in mated , unmated males and identified within the reproductive tract of mated but not virgin females. We also identified 42 more candidates that are likely Sfps based on their abundance, known expression and predicted characteristics, and revealed that four proteins previously identified as Sfps are at best minor contributors to the ejaculate. The estimated copy numbers for our candidate Sfps were lower than for previously identified Sfps, supporting the idea that our technique provides a deeper analysis of the Sfp proteome than previous studies. Our results demonstrate a novel, high-sensitivity approach to the analysis of seminal fluid proteomes, whose application will further our understanding of reproductive biology.
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http://dx.doi.org/10.1074/mcp.RA118.000831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427238PMC
March 2019

Seminal fluid.

Curr Biol 2017 Jun;27(11):R404-R405

Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

Seminal fluid does more than transport sperm. Hopkins et al., describe the diverse features and functions of seminal fluid, and its role in evolution and medicine.
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http://dx.doi.org/10.1016/j.cub.2017.03.063DOI Listing
June 2017

Hunk/Mak-v is a negative regulator of intestinal cell proliferation.

BMC Cancer 2015 Mar 8;15:110. Epub 2015 Mar 8.

University of Cardiff, European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff, CF10 3AX, UK.

Background: Conditional deletion of the tumour suppressor gene Apc within the murine intestine results in acute Wnt signalling activation. The associated over-expression of a myriad of Wnt signalling target genes yields phenotypic alterations that encompass many of the hallmarks of neoplasia. Previous transcriptomic analysis aimed at identifying genes that potentially play an important role in this process, inferred the Hormonally upregulated Neu-associated kinase (HUNK/Mak-v/Bstk1) gene as a possible candidate. Hunk is a SNF1 (sucrose non fermenting 1)-related serine/threonine kinase with a proposed association with many different tumour types, including colorectal cancer.

Methods: Here we describe the generation of a novel Hunk kinase deficient mouse which has been used to investigate the involvement of Hunk-kinase activity in intestinal homeostasis and tumourigenesis.

Results: We show that in the morphologically normal intestine, Hunk-kinase negatively regulates epithelial cell proliferation. However, the increase in cell proliferation observed in the Hunk kinase deficient intestine is counteracted by increased cell migration, thereby maintaining intestinal homeostasis. Using qRT-PCR, we further demonstrate that Hunk is significantly over-expressed in Apc deficient / Wnt-signalling activated intestinal tissue. Using the classical intestinal tumourigenesis Apc (Min) mouse model we show that loss of Hunk-kinase activity significantly reduced tumour initiation rates in the small intestine. However, an accompanying increase in the size of the tumours counteracts the impact this has on overall tumour burden or subsequently survival.

Conclusions: In the intestinal setting we demonstrate that Hunk has a role in normal intestinal proliferation and homeostasis and, although it does not alter overall survival rates, activity of this kinase does impact on tumour initiation rates during the early stages in tumourigenesis in the small intestine.
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http://dx.doi.org/10.1186/s12885-015-1087-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367870PMC
March 2015